N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization

Lemke, Carina; Cianni, Lorenzo; Feldmann, Christian; Gilberg, Erik; Yin, Jiafei; Rocho, Fernanda dos Reis; Vita, Daniela De; Bartz, Ulrike; Bajorath, Jürgen; Montanari, Carlos Alberto; Gütschow, Michael

doi:10.1016/j.bmcl.2020.127420

Cited by 5 publications

(2 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the contrary, the compounds were highly potent inhibitors of CatS. This finding was expected because leucine is known as a preferred P2 amino acid in CatS substrates and the Leu-Phe dipeptide as an advantageous P2–P1 pattern in peptidomimetic CatS inhibitors. ,, The majority of compounds did not show CatB inhibition, and 5b , 11b , 12a , and 14a exhibited K i values in the range of 9 to 22 μM. These four compounds inhibited CatS with K i values between 5 and 118 nM.…”

Section: Resultsmentioning

confidence: 99%

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Flury,

Breidenbach,

Krüger

et al. 2024

ACS Pharmacol. Transl. Sci.

Self Cite

View full text Add to dashboard Cite

Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series of 21 peptidomimetics and evaluated their inhibitory activity against human cathepsins L, B, and S. Structural diversity was realized by combinations of different C-terminal warhead functions and N-terminal capping groups, while a central Leu-Phe fragment was maintained. Several compounds were identified as promising cathepsin L and S inhibitors with K i values in the low nanomolar to subnanomolar range, for example, the peptide aldehydes 9a and 9b (9a, 2.67 nM, CatL; 0.455 nM, CatS; 9b, 1.76 nM, CatL; 0.512 nM, CatS). The compounds' inhibitory activity against the main protease of SARS-CoV-2 (M pro ) was additionally investigated. Based on the results at CatL, CatS, and M pro , selected inhibitors were subjected to investigations of their antiviral activity in cell-based assays. In particular, the peptide nitrile 11e exhibited promising antiviral activity with an EC 50 value of 38.4 nM in Calu-3 cells without showing cytotoxicity. High metabolic stability and favorable pharmacokinetic properties make 11e suitable for further preclinical development.

show abstract

Section: Resultsmentioning

confidence: 99%

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Flury,

Breidenbach,

Krüger

et al. 2024

ACS Pharmacol. Transl. Sci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This finding was expected because leucine is known as a preferred P2 amino acid in CatS substrates and the Leu-Phe dipeptide as an advantageous P2-P1 pattern in peptidomimetic CatS inhibitors. [41][42][43] The majority of compounds did not show CatB inhibition, and 5b, 11b, 12a, and 14a exhibited Ki values in the range of 9 µM to 22 µM. These four compounds inhibited CatS with Ki values between 5 nM and 118 nM.…”

Section: Scheme 2 Synthesis Ofmentioning

confidence: 98%

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Flury,

Breidenbach,

Krüger

et al. 2023

Preprint

View full text Add to dashboard Cite

Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series of 21 peptidomimetics and evaluated their inhibitory activity against human cathepsins L, B, and S. Structural diversity was realized by combinations of different C-terminal warhead functions and N-terminal capping groups, while a central Leu-Phe fragment was maintained. Several compounds were identified as promising cathepsin L and S inhibitors with Ki values in the low nanomolar to subnanomolar range, for example, the peptide aldehydes 9a and 9b (9a, 2.67 nM, CatL; 0.0455 nM, CatS; 9b, 1.76 nM, CatL; 0.0512 nM, CatS). The compounds’ inhibitory activity against the main protease of SARS-CoV-2 (Mpro) was additionally investigated. Based on the results at CatL, CatS, and Mpro, selected inhibitors were subjected to investigations of their antiviral activity in cell-based assays. In particular, the peptide nitrile 11e exhibited promising antiviral activity with an EC50 value of 35.1 nM in Calu-3 cells without showing cytotoxicity. High metabolic stability and favorable pharmacokinetic properties make 11e suitable for further preclinical development.

show abstract

Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L

Cianni

Rocho

Bonatto

et al. 2021

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization

Cited by 5 publications

References 34 publications

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L

Contact Info

Product

Resources

About